Combating the Threat of Pandemic Influenza: Drug Discovery Approaches

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Preparing for an Influenza Pandemic, A CDC Perspective

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Combating the Threat of Pandemic Influenza Drug Discovery Approaches

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Cell Host Microbe. Gene expression signature-based screening identifies new broadly effective influenza a antivirals. Repurposing of drugs as novel influenza inhibitors from clinical gene expression infection signatures. Future Virol. HTS antiviral screening algorithm. One advantage of a cell based assay is that it can identify compounds that are effective against known and unknown targets, as well as identify compounds that are metabolized by the cell into effective antivirals.

Disadvantages include an inability to recognize effective but toxic compounds, compounds that are excluded from passage through the cellular membrane, or compounds that inhibit through aggregation-based mechanisms. The growing use of cell-based assays is balanced by the technical challenges in developing robust, large-scale systems—that is, the laborintensive production of large quantities of cells and the inherent assay variability due to differences in cell passage number and handling.

CPE induced by viral infection is a well-documented and frequently exploited determinant for viral propagation in lytic viruses, but one which requires a reliable method for determining viability. A variation of this assay that could be adapted to screen large libraries has been demonstrated more recently using CV-1 cells that have been infected with a high titer of SV40 virus containing the M2 cDNA sequence.

This assay format is suitable for miniaturization, as well as for automation of liquid handling and reading, and is fully adaptable to HTS as both a primary or secondary assay. Biochemical HTS Assays. For HTS primary antiviral screening, biochemical assays can often be performed in a fraction of the time hours instead of days that a cell-based assay can, and they are not bound by compound toxicity issues, making them ideal for targeted primary HTS. An effective and sensitive NA assay that directly measures sialidase activity instead of indirectly by enzyme cascade, as detailed in Ref.

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After a minute incubation to allow for the compounds to potentially bind to the NA on the surface of the virus, the substrate is diluted in reaction buffer and added to the plates, allowed a minute reaction time, and stopped by addition of a high-pH stop buffer. This method has recently succeeded in identifying novel NA inhibitors.

The HA protein is instrumental during the initial stages of infection, and therefore a cell-based primary HTS assay would serve to screen compounds for the target activities that are associated with HA—that is, the surface glycoprotein sialic acid recognition, membrane fusion that is mediated by the HA2 fusion peptide, and activation by protease cleavage of HA0.

The lack of HA-associated catalytic activity makes HTS assay development a challenge that depends heavily on the chosen target and method of endpoint. This method might be adapted to target small molecules that inhibit membrane fusion of the HA2 peptide, thereby rapidly surveying and identifying effective small molecule combinations from large compound libraries. These assays have utilized UV-crosslinking to capture RNA-protein binding and electrophoretic detection to examine the reaction products.

This assay has been adapted to a well microplate format, and the addition of automated robotics would allow several thousand compounds to be screened by scintillation counting in a single day.

The protein- and RNA-binding potential of NS1 is an elusive activity to target for inhibition by small molecules, although inhibition by both RNA aptamers and short peptides has been proposed. However, these assays have not been developed or validated for HTS at this time. Assay throughput will certainly be reduced at high biosafety in favor of increased safety. Kiselar, J. Biochemistry , 38, — Thompson, W. Szucs, T. B, 11— Meltzer, M. Phipps, L. Methods , , — United States Department of Agriculture. Vahlenkamp, T. Olsen, B. Layne, S. Hao, W. Development of a novel dicistronic reporter-selectable hepatitis C virus replicon suitable for high-throughput inhibitor screening.

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Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs

Molecular Probes , A, 1—3. Blick, T. Varghese, J. Liu, A. China C. Life Sci. Szecsi, J. Targeted retroviral vectors displaying a cleavage site-engineered hemagglutinin HA through HA-protease interactions. Brownlee, G. Bhat, J. Wang, Y. Chien, C. Biochemistry , 43, — Prevention, C. Ghosh, R. It can be divided into three types, A, B, and C, of which A is the primary pathogen for humans. Upon binding to the cell surface receptor, the virus enters by endocytosis. Once in the endosome, low pH mediates the fusion of the viral and endosome membranes so that the viral nucleocapsids are released into the cytoplasm and then imported into the cell nucleus.

After translation in the cytoplasm, the viral proteins are then transported back to the nucleus to initiate replication of the genome and secondary mRNA transcription. Subsequently, viral ribonucleoprotein complexes are assembled in the nucleus and then transported to the plasma membrane where budding of mature virions occurs. Type I interferon is immediately induced upon viral infection and subsequently leads to the induction of hundreds of genes that collectively create an antiviral state in the cell.

It resides in the perinuclear region and is believed to inhibit nuclear import and cell-cycle progression. It exists at low levels in most cell types and is potently induced by IFN. NS1 is a NS1 mediates this by binding a purinecontaining bulge in a stem structure of the splicesomal U6 small nuclear RNA. Therefore, inhibition of total cellular gene expression would also inhibit ISG induction. This may suggest that conducting similar experiments in other strains of mice may provide more insight into other potential mediators of host defense.

Although some PKR protein is nuclear, it is predominantly detected in the cytoplasm, and therefore nuclear sequestration of dsRNA could effectively prevent it from activating PKR. It contains nine tandemly arranged tetratricopeptide repeats TPR as well as a J-domain that shares homology with the DnaJ heat shock family of proteins.

Hsp40 inhibition of PKR may involve a third component, Hsp Preliminary results have been noted in a review by Kash et al. PERK is activated by the build-up of misfolded proteins in the endoplasmic reticulum, which is known to induce the unfolded protein response UPR. Despite the overlap, ISG15 and dsRNA can bind simultaneously and the binding of one has no appreciable effect on the other. The OAS and RNase L proteins function in tandem as a sensor and effector mechanism, respectively, that ultimately leads to the cleavage of both cellular and viral RNAs to inhibit virus replication.

OAS is activated by viral dsRNA, typically produced during viral genome replication or the transcription of viral genes. This analysis showed no inhibition by the mutated virus and concluded that dsRNA binding was not involved in the suppression of IFN. The R38A mutation used in both studies is located in the common NLS and therefore may differentially affect subcellular localization of the two mutant NS1 proteins.

IFN, in combination with the nucleoside analogue ribavirin, is currently the primary therapeutic regimen for hepatitis C virus. Likewise, targeting the NS1 protein directly could also be a key strategy. Russell, C. Cell , , — Lamb, R. Orthomyxoviridae: The viruses and their replication. Ronni, T. Plotch, S. Cell , 23, — USA , 76, — Fortes, P. Park, Y. Hinshaw, V. Ikeda, H. The critical role of type-1 innate and acquired immunity in tumor immunotherapy. Cancer Sci. Stark, G.

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Seo, S. Most of those agents belong to the families orthomyxoviridae, paramyxoviridae, picornaviridae, coronaviridae, adenoviridae, and so on. Among them, the orthomyxoviruses and paramyxoviruses share a common nature, that is, they have negative-strand RNA and have viral envelopes with a plasma membrane structure, and they are similar in several steps of viral replication. In Table 4. Most human viral respiratory infections are highly contagious and sometimes epidemic. Dead cells are unable to reduce MTT to formazan. In addition, colorimetric assays facilitate the mass screening of compounds and computerization of the obtained data.

We found that the critical points for the sensitive colorimetric method are as follows: First, the cells have to be used in a suspended state; second, cells, virus, and diluted compounds have to be introduced simultaneously to the culture plate; and third, the plate has to be centrifuged at g for 10 min before incubation. As shown in Table 4. TABLE 4. Figure 4.

Thus, both the LDH and MTT methods were proven to be applicable for the titration and evaluation of the antiviral activity of compounds for these viruses. The use of suspended cells and centrifugation at low speed were requisites for the colorimetric antiviral assay of myxoviruses. Among these, pyrazofurin, 3-deazaguanine, and ribavirin emerged as selective antiRSV agents Fig. Chemical structures of the nucleoside analogues that have anti-myxovirus activity. Pyrazofurin and 3-deazaguanine inhibited virus growth in HEp-2 cells at 0. Ribavirin has been approved for the clinical treatment of RSV infection as aerosol inhalation.

Thus pyrazofurin and 3-deazaguanine appeared to be candidate anti-RSV agents in addition to ribavirin. This report indicates that pyrazofurin was more toxic for chick embryos than ribavirin. Untreated Treated with Pyrazofurina,b 1 2 3 4 5 Average There was no obvious toxicity for rats. Long A. FM A. NS B. Sendai Fushimi 2. CA Greer 3. Bangkok H1N1 A. Ishikawa H3N2 B. Their EC50s for paramyxovirus except for RSV in vitro were to fold less than that of ribavirin. Finally, mizoribin is a compound that has been applied clinically as an immunosuppressive drug.

Sulfated Polysaccharides Sulfated polysaccharides such as dextran sulfate have been reported to be potent and selective inhibitors of several envelope viruses. Hosoya et al. Although we were not able to analyze the sugar sequence of the polysaccharide, the composition of the sugar moiety was analyzed. The molar ratio of sugars in OKU is glucose 1. OKU and OKU are noncytotoxic substances whereas we were concerned about their anti-coagulating effect on normal plasma.

APTT, activated partial thromboplastin time. OKU and are nontoxic and broad-spectrum anti-myxovirus substances. Since these substances exist abundantly in nature and are easy to extract from microorganisms, it is worth of investigating them further to develop anti-myxovirus drugs from these substances. Polyoxometalates Polyoxometalates POM are soluble inorganic cluster-like compounds formed principally of an oxide anion and early transition metal cations such as tungsten W , molybdenium Mo , niobium Nb , antimony Sb , vanadium V , and so on.

HS inhibited both adsorption and the fusion process of RSV infection, whereas it only inhibited the fusion process of FLUV to the cellular membrane. Six compounds showed SIs of more than Among these compounds, PM, , , and were V-containing polyoxotungstates and PM, , were Ticontaining polyoxotungstates. Coronavirus is a positive-strand RNA virus and is covered with an envelope that is obtained at the release of the virus from the cell membrane.

Coronaviruses are infectious in a number of animals, namely, pigs, cattle, cats, birds, and so on. A coronavirus that infects humans causes a severe, sometimes mortal respiratory disease called SARS. Table 4. The abscissa indicates intensity of populations of infected cells and the ordinate indicates the number of cells. The rightmost line is a population of infected cells without compounds, and the leftmost line is that of uninfected cells.

See color insert. EC50 was determined by the plaque reduction method. For other viruses it was determined by the MTT method. PM and PM had Keggin sandwich structures. The SIs greater than 30 are indicated in boldface. PM, , and have particular structures—that is, Keggin dimmer, Lindqvist triangle, and Keggin triangle, respectively. Antisense sequences are underlined. R represents an alkyl loop hexa-ethylene glycol structure. For the delivery of antisense ODN, they used liposome encapsulation of the materials.

The former is designated RBI and the latter is commercialized as palivizumab. Both compounds interacted with the early adsorption and late stages probably fusion and penetration of virus replication. We also examined the antiRSV activity of both compounds in vivo, using intranasal infection of RSV to cotton rats or immunosuppressed mice by cyclophosphamide injection.

RD was administrated as an aerosol for 2 hours twice daily 1. Anti-RSV compounds. Top: NMSO3. Bottom: RD Fresh clinical strain. When the section of infected lung was observed histologically, the evidence of interstitial pneumonia observed in untreated animals i. However, I am still adhering to the broadspectrum anti-respiratory virus agents for the reasons cited above. Since ribavirn is a broad-spectrum anti-myxovirus compound, synergistic effects were mainly examined between ribavirin and the other compounds.

The effect of the combination of PM and ribavirin on FLUV replication was evaluated by median-effect principle and isobologram, and it was analyzed by using a microcomputer with dose—effect analysis software. When we examined the in vitro combination effects and calculated the CI in several ratios of combination of PM and ribavirin, the CI was consistently lower than 1. As shown in Fig. Combination of PM and ribavirin at a ratio of 1 : 16 —— and 1 : 4 were analyzed under mutually nonexclusive assumptions.

Figures 4. These compounds exceeded ribavirin in the potency and selectivity of their anti-myxovirus effects in vitro. Combination index with respect to the fraction affected by the inhibition of a measles virus multiplication in Vero cells and b mumps virus in Vero cells. Mice were infected with virus 1. The compounds were given to the infected mice every 12 hr for 4 days starting at 8 hr after viral inoculation.

The materials were injected 2 mm deep with a gauge needle at two hr intervals into the subarachnoid space of hamsters under ether anesthesia. The author thanks for the technical assistance of Dr. Klein, M. The impact of infection with human metapneumovirus and other respiratory viruses in young infants and children at high risk for severe pulmonary disease. Lamson, D. George, K.

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Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches
Combating the Threat of Pandemic Influenza: Drug Discovery Approaches Combating the Threat of Pandemic Influenza: Drug Discovery Approaches

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